The present invention relates to treating agents for osteoarthritis, comprising as an active ingredient, a compound represented by the formula (I): ##STR2## wherein R represents a hydrogen atom or an acyl group, X represents a CHO group, a COOH group or a physiologically acceptable salt thereof, or a CH(OR').sub.2 group wherein R' represents an acyl group.
As an arthrosis, rheumatiod arthritis, rheumatic fever and osteoarthritis have been popular so far and especially there were many patients suffering from rheumatiod arthritis or rheumatic fever and these two disorders have been studied since the two diseases were the main subject matter among arthrosis. However, recently, in proportion of an increase of aged people in the total population, patients suffering from a primary osteoarthritis due to a senescence of a joint, especially to a deformation of cartilage by detrition are increasing and accordingly the disease becomes a subject of watching by many physicians.
Up to now, among the compounds represented by the formula (I), 3,4-dialkanoyloxybenzylidene dialkanoate including 3,4-diacetoxybenzylidene diacetate (hereinafter referred to as "ACP"), 3,4-dialkanoyloxybenzaldehyde including 3,4-dihydroxybenzaldehyde (hereinafter referred to as "PAL") and 3,4-dialkanoyloxybenzoic acid including 3,4-dihydroxybenzoic acid (hereinafter referred to as "PAC") have been known effective as anti-inflammatory agents, treating agents for nephritis, anti-cancer agent and agents for suppressing fibrogenesis. For example, U.S. Pat. No. 4,758,591 discloses ACP as an anti-inflammatory agent, Japanese Patent Application (hereinafter referred to as "JP-A"), Laid-Open (KOKAI) No. 55-51,018 (1980) does PAL as an anti-cancer agent, JP-A, Laid-Open (KOKAI) No. 58-83,619 (1983) does PAL as an anti-inflammatory agent, JP-A, Laid-Open (KOKAI) No. 59-196,818 (1984) does PAL as an anti-nephritis agent and U.S. Pat. No. 4,248,892 does PAC as an anti-fibrogenesis agent.
Further, U.S. Pat. No. 4,758,591 describes that 3,4-dialkanoyloxybenzylidene dialkanoate including ACP, and PAL are appropriate agents treating inflammatory; rheumatic disease such as rheumatoid arthritis; and autoimmune diseases such as glomerular nephritis or systemic lupus erythematosus; since they exhibit suppressing activity of leukocyte migration, granuloma proliferation and adjuvant arthritis and further they are very low toxic to mammals including human. However, the above references do not say anything at all about osteoarthritis.
Osteoarthritis is a retroplasia occurred in a joint and there are a secondary one due to an congenital hypoplasia, trauma or other diseases and a primary one due to a retroplasia of joint cartilage. In general, osteoarthritis occurs mostly at a joint more or less supporting body weight. A secondary and congenital one are found frequently at a hip joint and a primary one due to senescences is found often at a joint of spine or a knee.
Osteoarthritis is sometimes classified as a rheumatic diseases in its broad meaning, but it is a different disease from so-called rheumatism such as rheumatoid arthritis and rheumatic fever. For example, a rheumatic fever is accompanied with a lesion in heart and a rheumatoid arthritis has an adhesion in the joint. However, osteoarthritis causes a deformation of cartilage of a joint but no adhesion in the joint nor a lesion in heart. Furthermore, rheumatoid arthritis is not limited to a joint having a load such as a knee joint or a hip joint and its pathopoiesis is often observed at a joint of hand or finger. Accordingly, osteoarthritis is different from rheumatism and should be classified separately from rheumatism.
Further, rheumatoid arthritis is a systemic disease and causes an inflammation in connective tissues and an administration of a conventional anti-inflammatory agent is a one of main treatments. In osteoarthritis, it also causes an inflammation in a synovial membrane but it is not a main lesion and accordingly simple administration of conventional anti-inflammatory agents does not give sufficient results for the treatment.
The present inventors have studied extensively to develop a pharmaceutical drug to treat osteoarthritis, which disease is gathering notice of many physicians since aging phenomena recently become remarkable throughout the advanced countries, and taking into their consideration a recent finding that interleukin 1 (hereinafter referred to as "IL-1") is noted as a joint cartilage destroying factor, they have created a concept that if they could develop a drug which is capable of suppressing a production or a release of IL-1 by macrophages, they would be able to attain the present invention.
Based on this concept, the inventors have studied earnestly and have found the facts that 3,4-dialkanoyloxybenzylidene dialkanoate including ACP, PAL, PAC and its physiologically acceptable salt have a strong activity to suppress a production and/or a release of IL-1. Further, they have also found the fact that the above compounds of the present invention can suppress a decomposition of cartilage matrix and a release of proteoglycan which is a main constituent of the cartilage, as its fragment. Based upon these supplemental findings, they have completed the present invention.